Method for the stereo-selective preparation of a derivative of β-phenyl-isoserine and its use in the preparation of taxane derivatives

ABSTRACT

A β-phenylisoserine derivative of general formula (I): ##STR1## in the form of a salt or an ester, in which Ar represent an aryl radical, R represents a phenyl or naphthyl or a O--R 1  radical and G 1  represents --CH 2  --Ph radical; and a method of using the same for making taxane derivatives.

This is a continuation of application Ser. No. 08/411,693 filed on Apr.5, 1995 now U.S. Pat. No. 5,726,346, which is a 371 of PCT/FR93/00966dated Oct. 4, 1993.

DESCRIPTION OF THE INVENTION

The present invention relates to a process for the stereoselectivepreparation of a β-phenylisoserine derivative of general formula:##STR2## in which Ar represents an aryl radical,

R represents a phenyl or α- or β-naphthyl radical optionally substitutedwith one or more identical or different atoms or radicals chosen fromhalogen atoms, alkyl radicals containing 1 to 4 carbon atoms and alkoxyradicals containing 1 to 4 carbon atoms, or a radical R₁ --O in which R₁represents:

an unbranched or branched alkyl radical containing 1 to 8 carbon atoms,an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radicalcontaining 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or abicycloalkyl radical containing 7 to 11 carbon atoms, these radicalsbeing optionally substituted with one or more substituents chosen fromhalogen atoms and hydroxyl radicals, alkyloxy radicals containing 1 to 4carbon atoms, dialkylamino radicals in which each alkyl portion contains1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinylradicals (optionally substituted at position 4 with an alkyl radicalcontaining 1 to 4 carbon atoms or with a phenylalkyl radical in whichthe alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicalscontaining 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6carbon atoms, phenyl, cyano or carboxyl radicals or alkyloxycarbonylradicals in which the alkyl portion contains 1 to 4 carbon atoms,

or a phenyl radical optionally substituted with one or more atoms orradicals chosen from halogen atoms and alkyl radicals containing 1 to 4carbon atoms or alkyloxy radicals containing 1 to 4 carbon atoms,

or a saturated or unsaturated 4- or 6-membered nitrogenous heterocyclicradical optionally substituted with one or more alkyl radicalscontaining 1 to 4 carbon atoms,

on the understanding that the cycloalkyl, cycloalkenyl or bicycloalkylradicals can be optionally substituted with one or more alkyl radicalscontaining 1 to 4 carbon atoms, and

G₁ represents a group protecting the hydroxyl function, chosen frommethoxymethyl, 1-ethoxyethyl, benzyloxymethyl,2,2,2-trichloroethoxymethyl, tetrahydrofuranyl, tetrahydropyranyl andβ-(trimethylsilyl)ethoxymethyl radicals, trialkylsilyl radicals in whichthe alkyl radicals contain 1 to 4 arbon atoms, or --CH₂ --Ph in which Phrepresents a phenyl radical optionally substituted with one or moreidentical or different atoms or radicals chosen from halogen atoms,alkyl radicals containing 1 to 4 carbon atoms and alkoxy radicalscontaining 1 to 4 carbon atoms.

Preferably, Ar represents a phenyl or α- or β-naphthyl radicaloptionally substituted with one or more atoms or radicals chosen fromhalogen (fluorine, chlorine, bromine, iodine) atoms and alkyl, alkenyl,alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio,hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino,alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl,alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro andtrifluoromethyl radicals, on the understanding that the alkyl radicalsand alkyl portions of the other radicals contain 1 to 4 carbon atoms,that the alkenyl and alkynyl radicals contain 3 to 8 carbon atoms andthat the aryl radicals are phenyl or α- or β-naphthyl radicals.

More especially, Ar represents a phenyl radical optionally substitutedwith one or more identical or different atoms or radicals chosen fromhalogen atoms and alkyl, alkoxy, amino, alkylamino, dialkylamino,acylamino, alkoxycarbonylamino and trifluoromethyl radicals.

Still more especially, Ar represents a phenyl radical optionallysubstituted with a chlorine or fluorine atom or with an alkyl (methyl),alkoxy (methoxy), dialkylamino (dimethylamino), acylamino (acetylamino)or alkoxycarbonylamino (tert-butoxycarbonylamino) radical.

Of even more special importance are the products of general formula (I)in which Ar represents a phenyl radical, R represents a phenyl ortert-butoxy radical and G₁ represents a benzyl or p-methoxybenzylradical.

The products of general formula (I), and especially those for which G₁represents --CH₂ --Ph, which are new products constituting anothersubject of the present invention, are especially useful for preparingtaxol or Taxotere and their analogues, by condensation with a baccatinIII or 10-deacetylbaccatin III derivative in which the hydroxylfunctions are suitably protected, working under the conditionsdescribed, for example, in European Patents EP 0,336,840 or EP0,336,841.

It is known to prepare analogues of the product of general formula (I)from a β-phenylglycidic acid by working, for example, under theconditions described in European Patent EP 0,414,610.

It has now been found that the products of general formula (I) may beobtained directly, with very good enantio- and diastereoselectivity, bycarrying out a process which requires far fewer steps to be carried outthan according to the previously known processes.

According to the present invention, the products of general formula (I)may be obtained by the action of an N-carbonylarylimine of generalformula:

    Ar--CH═N--CO--R                                        (II)

in which Ar and R are defined as above, on the anion of an opticallyactive amide of a protected hydroxyacetic acid, of general formula:##STR3## in which G₁ is defined as above and ##STR4## represents theresidue of an optically active organic base, followed by hydrolysis ofthe product thereby obtained, of general formula: ##STR5## in which R,Ar, G₁ and ##STR6## are defined as above.

It is especially advantageous to use an amide of general formula (III)in which ##STR7## represents an L(+)-2,10-camphorsultam residue offormula: ##STR8##

The process according to the invention is generally carried out byreacting the N-carbonyl-arylimine of general formula (II), optionallyprepared in situ, with the previously anionized amide of the protectedhydroxyacetic acid. The anionization is generally effected by means ofan alkali metal amide. Amongst suitable amides, there may be mentionedsodium bis(trimethylsilyl)amide (NHMDS), lithiumbis(trimethylsilyl)amide (LHMDS) or potassium bis(trimethylsilyl)amide(KHMDS), lithium diisopropylamide (LDA), lithium diethylamide (LDEA),lithium dicyclohexylamide (LDCHA), (CH₃)₃ SiN(R')Li (R'=alkyl,cycloalkyl, aryl) and tBuLi. Of very special importance is lithiumbis(trimethylsilyl)amide which enables a high yield and excellentstereoselectivity to be obtained.

Generally, the anionization is performed in an inert organic solvent,for instance an ether such as tetrahydrofuran, at a temperature below 0°C. and preferably in the region of -78° C.

The action of the product of the general formula (II) on the previouslyanionized product of general formula (III) is generally performed in thesame solvent and at the same temperature.

The product of general formula (IV) is hydrolysed to the product ofgeneral formula (I) by means of an inorganic base such as sodiumhydroxide, potassium hydroxide or lithium hydroxide in an aqueous oraqueous-organic medium. It is especially advantageous to work in atetrahydrofuran/water mixture in the presence of hydrogen peroxide. Thereaction temperature is generally between -10 and 20° C., and preferablyin the region of 0° C.

The N-carbonylarylimine of general formula (II) in which Ar is definedas above and R represents a t-butoxy radical is a new product whichconstitutes another subject of the present invention.

The N-carbonylarylimine of general formula (II) may be obtained by theaction of an optionally substituted benzoyl halide or a reactivederivative of general formula:

    R.sub.1 --O--CO--X                                         (VI)

in which R₁ is defined as above and X represents a halogen (fluorine,chlorine) atom or a residue --O--R₁ or --O--CO--OR₁, on a product ofgeneral formula:

    Ar--CH═N--Z                                            (VII)

in which Ar is defined as above and Z represents a reactive group, forinstance a trialkylsilyl radical such as a trimethylsilyl radical.

Generally, the action of the optionally substituted benzoyl halide orthe product of general formula (VI) on the product of general formula(VII) is performed by heating in an organic solvent, for instance anester such as ethyl acetate or a halogenated aliphatic hydrocarbon suchas dichloromethane or chloroform or an aromatic hydrocarbon such astoluene or benzene.

The imine of general formula (VII) may be obtained from the aldehyde ofgeneral formula:

    Ar--CHO                                                    (VIII)

in which Ar is defined as above, according to known methods. Forexample, the product of general formula (VII) in which Z represents atrimethylsilyl radical may be obtained according to D. J. Hart et al.,J. Org. Chem., 48, 289 (1983), by the action of lithiumbis(trimethyldisilyl)amide (LHMDS), optionally prepared in situ by theaction of butyllithium on bis(trimethylsilylamine), on the correspondingaldehyde of general formula (VIII).

The N-carbonylarylimine of general formula (II) may also be prepared insitu by the action of a strong base, for instance an amide such aslithium bis(trimethylsilyl)amide, on a thioether of general formula:##STR9## in which Ar and R are defined as above.

The optically active amide of general formula (III) may be obtained bythe action of an activated derivative of a protected hydroxyacetic acidof general formula:

    G.sub.1 --O--CH.sub.2 --COOH                               (X)

in which G₁ is defined as above, such as the halide or anhydride, on theoptionally anionized corresponding chiral base.

The product of general formula (I) may be used to prepare thetherapeutically active taxane derivatives of general formula: ##STR10##in which Ar and R are defined as above and R₄ represents a hydrogen atomor an acetyl radical, in a process which consists in reacting a productof general formula (I) with a baccatin III or 10-deacetylbaccatin IIIderivative of general formula: ##STR11## in which G₂ represents a groupprotecting the hydroxyl function, such as a2,2,2-trichloroethoxycarbonyl or trialkylsilyl radical, and R'₄represents an acetyl radical or a group protecting the hydroxylfunction, such as a 2,2,2-trichloroethoxycarbonyl radical, to obtain aproduct of general formula: ##STR12## in which R, Ar, G₁, G₂ and R'₄ aredefined as above, the protective groups G₁, G₂ and, where appropriate,R'₄ of which are replaced by hydrogen atoms, simultaneously orsuccessively.

Generally, the esterification of a product of general formula (XII) witha product of general formula (I) is performed in the presence of acondensing agent, for instance a carbodiimide such asdicyclohexylcarbodiimide or a reactive carbonate such as 2-pyridylcarbonate, and an activating agent, for instance an aminopyridine suchas 4-(dimethylamino)-pyridine or 4-pyrrolidinopyridine, working in anorganic solvent such as an aromatic hydrocarbon (benzene, toluene,xylene, ethylbenzene, isopropylbenzene, chlorobenzene), an ether(tetrahydrofuran), a nitrile (acetonitrile) or an ester (ethyl acetate),at a temperature of between 0 and 90° C.

When G₁ represents a methoxymethyl, 1-ethoxyethyl, benzyloxymethyl,2,2,2-trichloroethoxy-methyl, tetrahydrofuryl, tetrahydropyranyl orβ-trimethylsilylethoxymethyl radical or a trialkylsilyl radical in whichthe alkyl radicals contain 1 to 4 carbon atoms, the replacement of theprotective groups G₁, G₂ and, where appropriate, R'₄ of the product ofgeneral formula (XIII) is performed either with zinc, optionally incombination with copper, in the presence of acetic acid or by means ofan inorganic or organic acid such as hydrochloric acid or acetic acidoptionally dissolved in an aliphatic alcohol containing 1 to 3 carbonatoms, in the presence of zinc, optionally in combination with copper,when one of the protective groups represents a2,2,2-trichloroethoxycarbonyl radical, or by treatment with an inorganicor organic acid such as hydrochloric acid or acetic acid optionallydissolved in an aliphatic alcohol containing 1 to 3 carbon atoms, whenone of the protective groups represents a silyl radical.

When G₁ represents a --CH₂ --Ph or, where appropriate, a benzyloxymethylradical, the replacement of the protective groups G₂ and, whereappropriate, R'₄ by hydrogen atoms is performed first, under theconditions described above, to obtain the product of general formula:##STR13## in which R, Ar and R₄ are defined as above, the Ph--CH₂ -- or,where appropriate, the benzyloxymethyl group of which is replaced by ahydrogen atom to obtain the product of general formula (XI).

The replacement of the Ph--CH₂ -- or, where appropriate, thebenzyloxymethyl group of the product of general formula (XIV) by ahydrogen atom is generally performed by hydrogenolysis by means ofhydrogen in the presence of a catalyst such as palladium black, workingin an organic solvent such as acetic acid at a temperature of between 0and 60° C., and preferably in the region of 40° C. It can beadvantageous to work under pressure and optionally in the presence of acatalytic amount of an acid such as perchloric acid. The samereplacement is also performed by the action ofdichlorodicyanobenzoquinone (DDQ) in an organic solvent such asdichloromethane or acetonitrile.

The taxane derivatives of general formula (XI) thereby obtained may beoptionally purified by application of the usual techniques.

EXAMPLES

The examples which follow illustrate the present invention.

Example 1

287 mg (0.79 mmol) of L-N-(benzyloxyacetyl)-2,10-camphorsultam and 3 cm³of anhydrous tetrahydrofuran are introduced under an argon atmosphereinto a 10-cm³ single-necked round-bottomed flask equipped with amagnetic stirrer system. The solution is cooled to -78° C., and 0.8 cm³(0.8 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran is then added dropwise. The mixture is left to react for1 hour at -78° C., and 248 mg (1.21 mmol) ofN-t-butoxycarbonylbenzylimine dissolved in 1.7 cm³ of anhydroustetrahydrofuran are then added. After 15 minutes of reaction at -78° C.,the reaction mixture is hydrolyzed by adding saturated aqueous ammoniumchloride solution. It is extracted twice with dichloromethane. Thecombined organic phases are washed twice with water, then once withsaturated aqueous sodium chloride solution and then dried over anhydrousmagnesium sulphate. After filtration and removal of the solvents underreduced pressure, a residue (578 mg) is obtained, which is purified bychromatography on silica gel, eluting with a hexane/ethyl acetatemixture (85:15 by volume). 294 mg (0.52 mmol) ofsyn-L(+)-N-(2-benzyloxy-3-t-butoxycarbonylamino-3-phenylpropionyl)-2,10-camphorsultam,the characteristics of which are as follows, are thereby obtained in a66% yield.

melting point: 79° C., then 130° C. (dichloromethane/hexane); opticalrotation: [α]²⁵ _(D) =+53° (c=0.98; chloroform) infrared spectrum(film): main characteristic absorption bands at 3450, 3050, 3020, 2975,1720, 1500, 1460, 1420, 1395, 1370, 1340, 1280, 1240, 1220, 1170, 1140,1100, 1070, 1020, 860, 810, 760, 750 and 700 cm⁻¹ proton NMR spectrum(300 MHz; CDCl₃ ; chemical shifts in ppm; coupling constants J in Hz):0.99 (s, 3H); 1.1-1.6 (m, 2H); 1.28 (s, 3H); 1.39 (s, 9H); 1.83-2.25 (m,5H); 3.51 (AB_(q), J_(AB) =13.7, δ_(A) -δ_(B) =21.4, 2H); 3.94-4.03 (m,1H); 4.36 (AB_(q), J_(AB) =11.4, δ_(A) -δ_(B) =120, 2H); 4.86 (broad s,1H); 5.33 (d, J=9.8, 1H); 5.60 (d, J=9.8, 1H); 6.9-7.05 (m, 2H);7.14-7.4 (m, 8H). ¹³ C NMR spectrum (75.47 MHz; CDCl₃): 19.97 (CH₃);20.64 (CH₃); 26.59 (CH₂); 28.24 (CH₃); 32.81 (CH₂); 37.53 (CH₂); 44.49(CH); 47.92 (C); 48.89 (C); 53.11 (CH₂); 55.70 (CH); 65.07 (CH); 72.47(CH₂); 79.32 (C); 81.29 (CH); 126.78 (CH); 127.17 (CH); 127.65 (CH);127.84 (CH); 128.09 (CH); 136.72 (C); 139.54 (C); 154.95 (C); 169.90(C).

66 mg (0.116 mmol) of the product obtained above and 1 cm³ of atetrahydrofuran/water mixture (4:1 by volume) are introduced under anargon atmosphere into a 10 cm³ single-necked round-bottomed flaskequipped with a magnetic stirrer system. The mixture is cooled to 0° C.,and 95 μl (0.93 mmol) of hydrogen peroxide containing 30% by volume and20 mg (0.48 mmol) of hydrated lithium hydroxide (LiOH.H₂ O) are thenadded. The mixture is left to react for 1 hour at 0° C. and then stirredfor 15 hours at 20° C. A solution of 117 mg (0.93 mmol) of sodiumsulphite in 0.7 cm³ of water is then added. After evaporation of thetetrahydrofuran, water is added, and the basic aqueous solution obtainedis then extracted 3 times with dichloromethane. The basic aqueous phaseis acidified to pH 1-2 by adding 2M aqueous hydrochloric acid solution,and is extracted 6 times with ethyl acetate. The combined organic phasesare washed with saturated aqueous sodium chloride solution and thendried over anhydrous magnesium sulphate. After filtration and removal ofthe solvent under reduced pressure, 30 mg (0.081 mmol) of(2R,3S)-2-benzyloxy-3-t-butoxy-carbonylamino-3-phenylpropionic acid, thecharacteristics of which are as follows, are obtained in a 70% yield:

infrared spectrum (film): characteristic absorption bands at 3700-2300,3450, 3300, 3075, 3050, 3025, 2975, 2925, 1720, 1660, 1510, 1500, 1450,1390, 1370, 1250, 1165, 1110, 1020, 860, 740 and 695 cm⁻¹ proton NMRspectrum (200 MHz; CDCl₃ ; chemical shifts in ppm; coupling constants Jin Hz): 1.42 (s, 9H); 4.20 (broad s, 1H); 4.52 (AB_(q), J_(AB) =11.6,δ_(A) -δ_(B) =65, 2H); 5.30 (distorted d, J=9.9, 1H); 5.78 (distorted d,J=9.4, 1H); 6.2 (broad s, 1H); 7.0-7.06 (m, 2H); 7.06-7.44 (m, 8H) ¹³ CNMR spectrum (50.3 MHz, CDCl₃): 28.24 (CH₃); 55.67 (CH); 72.90 (CH₂);79.84 (CH); 80.49 (C); 126.60 (CH); 127.50 (CH); 127.95 (CH); 128.30(CH); 136.40 (C); 139.36 (C); 155.66 (C); 173.08 (C). elemental analysis(C₂₁ H₂₅ O₅ N)

    ______________________________________                                        calculated                                                                             C %    67.91    H %  6.78   N %  3.77                                  found  67.67  6.68  3.87                                                    ______________________________________                                    

N-(t-Butoxycarbonyl)benzylimine may be prepared in the following manner:

20 cm³ (95 mmol) of freshly distilled bis(trimethylsilyl)amine areintroduced under an argon atmosphere into a 100-cm³ single-neckedround-bottomed flask equipped with a magnetic stirrer system, and thencooled to 0° C. 34 cm³ (85 mmol) of a 2.5M solution of n-butyllithium inhexane are then added dropwise. The temperature is allowed to rise to avalue in the region of 20° C. and the mixture is then left to react for10 minutes. It is cooled to 0° C., and 8.63 cm³ (85 mmol) of freshlydistilled benzaldehyde are then added. The mixture is left to react at0° C. for 3 hours 30 minutes. After removal of the solvent under reducedpressure, the residue is distilled under reduced pressure. 13.8 g (78mmol) of N-(trimethylsilyl)benzylimine, the characteristics of which areas follows, are thereby obtained in a 92% yield:

infrared spectrum (film): main characteristic absorption bands at 3050,3020, 2950, 2900, 2800, 2700, 1650, 1600, 1580, 1450, 1300, 1250, 1210,1160, 1070, 1020, 970, 860, 840, 750 and 690 cm⁻¹ proton NMR spectrum(200 MHz; CDCl₃): 0.3 (s, 9H); 7.42-7.56 (m, 3H); 7.77-7.90 (m, 2H);9.02 (s, 1H).

2.92 g (16.5 mmol) of the imine obtained above and then 50 cm³ ofanhydrous chloroform are introduced under an argon atmosphere into a100-cm³ single-necked round-bottomed flask equipped with a magneticstirrer system. The mixture is cooled to 0° C., and 6.93 g (31.8 mmol)of pure di-t-butyl dicarbonate are then added dropwise. The reactionmixture is heated to reflux for 12 hours.

After removal of the chloroform under reduced pressure, the residue isdistilled under reduced pressure (1.3 Pa) at 103-105° C. 1.91 g (9.3mmol) of N-(t-butoxycarbonyl)benzylimine, the characteristics of whichare as follows, are thereby obtained in a 56% yield:

infrared spectrum (film): 3050, 2970, 2925, 1730, 1650, 1605, 1590,1485, 1460, 1320, 1275, 1260, 1220, 1155, 1000, 980, 885, 850, 755, 690cm⁻¹ proton NMR spectrum (200 MHz, CDCl₃): 1.61 (s, 9H); 7.44-7.60 (m,3H); 7.9-8.0 (m, 2H); 8.9 (s, 1H).

L-N-(Benzyloxyacetyl)-2,10-camphorsultam may be prepared in thefollowing manner:

181 mg (0.84 mmol) of L(+)-10,2-bornanesultam dissolved in 2 cm³ ofanhydrous toluene are introduced under an argon atmosphere into a 10-cm³single-necked round-bottomed flask equipped with a magnetic stirrersystem. The mixture is cooled to 0° C., and 50 mg (1.25 mmol) of 60%sodium hydride dispersed in mineral oil are then added. The mixture isleft to react to 30 minutes at 0° C., and 0.17 cm³ (1.08 mmol) ofbenzyloxyacetyl chloride is then added. The temperature is allowed torise to 20° C. and the mixture is then left to react for 2 hours. Thereaction mixture is diluted by adding dichloromethane, and water is thenadded slowly. The organic phase, separated after settling has takenplace, is washed with water and then with saturated aqueous sodiumchloride solution and finally dried over anhydrous magnesium sulphate.After filtration and removal of the solvents under reduced pressure, 511mg of an oily residue are obtained, which residue is purified bychromatography on a column of silica gel, eluting with a hexane/ethylacetate mixture (80:20 by volume). 294 mg (0.81 mmol) ofL-N-(benzyloxyacetyl)-2,10-camphorsultam, the characteristics of whichare as follows, are thereby obtained in a 97% yield:

infrared spectrum (film): main characteristic absorption bands at 2980,2970, 1710, 1460, 1420, 1395, 1340, 1270, 1245, 1225, 1170, 1140, 1115,1065, 1040, 1030, 985, 950, 870, 800, 780, 750 and 700 cm⁻¹ proton NMRspectrum (200 MHz; CDCl₃): 0.96 (s, 3H); 1.13 (s, 3H); 1.2-1.6 (m, 2H);1.6-2.3 (m, 5H); 3.3-3.6 (m, 2H); 3.8-4.0 (m, 1H); 4.4-4.75 (m, 4H);7.1-7.5 (m, 5H).

Example 2

42 mg (0.115 mmol) of L-N-(benzyloxyacetyl)-2,10-camphorsultam and 0.4cm³ of anhydrous tetrahydrofuran are introduced under an argonatmosphere into a 5-cm³ single-necked round-bottomed flask equipped witha magnetic stirrer system. The mixture is cooled to -78° C., and 115 μl(0.115 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran are then added. The mixture is left to react for 1 hourat -78° C., and 72 mg (0.23 mmol) ofN-t-butoxycarbonyl-α-(phenylthio)benzylamine and 230 μl (0.23 mmol) of a1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran arethen added. The reaction mixture is left to react for 1 hour 30 minutesat -78° C., and is then hydrolyzed by adding saturated aqueous ammoniumchloride solution. The temperature is allowed to rise to 20° C. and themixture is then extracted 3 times with ether. The combined organicphases are washed twice with water and then once with saturated aqueoussodium chloride solution and then dried over anhydrous magnesiumsulphate. After filtration and removal of the solvents under reducedpressure, the residue obtained (114 mg) is purified by chromatography ona column of silica gel, eluting with a hexane/ethyl acetate mixture(85:15 by volume).

35 mg (0.062 mmol) ofsyn-L(+)-N-(2-benzyloxy-3-t-butoxycarbonylamino-3-phenylpropionyl)-2,10-camphorsultam,the characteristics of which are identical to those of the productobtained in Example 1, are thereby obtained in a 54% yield.

Example 3

94 mg (0.253 mmol) of(2R,3S)-2-benzyloxy-3-t-butoxycarbonylamino-3-phenylpropionic aciddissolved in 3.5 cm³ of anhydrous toluene are introduced under an argonatmosphere into a 10-cm³ single-necked round-bottomed flask equippedwith a magnetic stirrer system. 52.3 mg (0.253 mmol) of distilleddicyclohexylcarbodiimide are then added. The mixture is left to reactfor 5 minutes at a temperature in the region of 20° C., and a mixture of7.7 mg (0.063 mmol) of 4-(N,N-dimethylamino)pyridine and 56.3 mg (0.063mmol) of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2-trichloroethoxycarbonyloxy)-11-taxeneis then added all at once. The mixture is left to react for 20 hours ata temperature in the region of 20° C. The reaction mixture is diluted byadding 40 cm³ of ethyl acetate. The organic phase is washed once with 5cm³ of distilled water, twice with 5 cm³ of saturated aqueous sodiumhydrogen carbonate solution and then once with 5 cm³ of saturatedaqueous sodium chloride solution and is finally dried over anhydroussodium sulphate. After filtration and removal of the solvents underreduced pressure, a residue (166 mg) is obtained, which is purified bychromatography on a column of silica gel, eluting with anether/dichloromethane mixture (1:99 by volume). 73 mg (0.0585 mmol) of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis(2,2,2-trichloroethoxycarbonyloxy)-11-taxen-13α-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-(benzyloxy)-propionate, thecharacteristics of which are as follows, are thereby obtained in a 93%yield:

optical rotation (repurified product) [α]²⁵ _(D) =-32° (c=0.86;chloroform) infrared spectrum (film): main characteristic absorptionbands at 3450, 3050, 2970, 2920, 2900, 1760, 1740, 1720, 1600, 1580,1490, 1450, 1375, 1242, 1175, 1165, 1100, 1060, 1000, 975, 960, 820,770, 720 and 700 cm⁻¹ proton NMR spectrum (200 MHz; CDCl₃ ; chemicalshifts in ppm; coupling constants J in Hz): 1.21 (s, 3H); 1.30 (s, 3H);1.35 (s, 9H); 1.8-2 (m, 1H); 1.86 (s, 3H); 2.01 (s, 3H); 2-2.2 (m, 2H);2.26 (s, 3H); 2.57-2.68 (m, 1H); 3.91 (d, J=7, 1H); 4.24 (s, 1H); 4.25(AB_(q), J_(AB) =8.7, δ_(A) -δ_(B) =43.8, 2H); 4.50 (AB_(q), J_(AB) =12,δ_(A) -δ_(B) =109, 2H); 4.76 (AB_(q), J_(AB) =11.8, δ_(A) -δ_(B) =91,2H); 4.78 (AB_(q), J_(AB) =12, δ_(A) -δ_(B) =7.6, 2H); 4.95 (distortedd, J=10.5, 1H); 5.14-5.36 (m, 1H); 5.4-5.6 (m, 1H); 5.57 (q, J=7.2 and10.7, 1H); 5.71 (d, J=7, 1H); 6.2-6.33 (m, 1H); 6.26 (s, 1H); 7-7.1 (m,2H aromatic); 7.22-7.86 (m, 11H aromatic); 8.06-8.11 (m, 2H aromatic).elemental analysis (C₅₆ H₆₁ O₁₈ NCl₆)

    ______________________________________                                        calculated                                                                             C %    53.86    H %  4.92   N %  1.12                                  found  53.75  5.15  1.32                                                    ______________________________________                                    

58 mg (0.0465 mmol) of the ester obtained above dissolved in 3 cm³ ofglacial acetic acid are introduced under an argon atmosphere into a10-cm³ single-necked round-bottomed flask equipped with a magneticstirrer system. 3 cm³ of methanol are then added, followed by 260 mg ofzinc/copper system (prepared from 20 g of zinc and 3 g of coppersulphate monohydrate). The black heterogeneous medium is heated to 65°C. for 30 minutes. After cooling to a temperature in the region of 20°C., the reaction mixture is diluted in 40 cm³ of ethyl acetate. It isfiltered through Celite, and the solids are then washed 3 times with 20cm³ of ethyl acetate. The solvents are removed under reduced pressure.The residue obtained is purified by preparative thin-layerchromatography on silica gel, eluting with a methanol/dichloromethanemixture (5:95 by volume). 38 mg of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-(benzyloxy)propionate, thecharacteristics of which are as follows, are obtained in a 91% yield:

infrared spectrum (film): characteristic absorption bands at 3430, 3050,2975, 2910, 2880, 1740, 1725, 1710, 1495, 1450, 1390, 1370, 1350, 1270,1240, 1160, 1105, 1065 and 980 cm⁻¹ proton NMR spectrum (200 MHz; CDCl₃; chemical shifts in ppm; coupling constants J in Hz): 1.14 (s, 3H);1.26 (s, 3H); 1.33 (s, 9H); 1.75 (s, 3H); 1.91 (s, 3H); 1.8-2.3 (m, 3H);2.24 (s, 3H); 2.46-2.73 (m, 1); 3.91 (d, J=7, 1H); 4.12-4.38 (m, 3H);4.20 (s, 1H); 4.51 (AB_(q), J_(AB) =12, δ_(A) -δ_(B) =71, 2H); 4.94 (d,J=7.5, 1H); 5.21 (s, 1H); 5.13-5.29 (m, 1H); 5.44-5.6 (m, 1H); 5.69 (d,J=7, 1H); 6.27 (distorted t, J=7.3 and 8.8, 1H); 7-7.1 (m, 2H aromatic);7.19-7.66 (m, 11H aromatic); 8.08-8.12 (m, 2H aromatic). elementalanalysis (C₅₀ H₅₉ O₁₄ N)

    ______________________________________                                        calculated                                                                             C %    66.87    H %  6.62   N %  1.56                                  found  66.65  6.72  1.73                                                    ______________________________________                                    

14 mg (0.0156 mmol) of the product obtained above dissolved in 1.6 cm³of glacial acetic acid are introduced under an argon atmosphere into5-cm³ single-necked round-bottomed flask equipped with a magneticstirrer system. 5 mg of palladium black are then added, and the mixtureis thereafter placed under a hydrogen atmosphere. It is heated andstirred at 40° C. and then left to react for 6 hours. After cooling to atemperature in the region of 20° C., the reaction mixture is diluted in5 cm³ of ethyl acetate. After filtration through Celite, the solids arewashed with 5 times 5 cm³ of ethyl acetate. The combined organic phasesare washed 3 times with 5 cm³ of saturated aqueous sodium hydrogencarbonate solution, 3 times with 5 cm³ of water and once with 5 cm³ ofsaturated aqueous sodium chloride solution and are then dried overanhydrous sodium sulphate. After filtration and removal of the solventsunder reduced pressure, the residue obtained (14 mg) is purified bypreparative thin-layer chromatography on silica, eluting with amethanol/dichloromethane mixture (5:95 by volume). 8.5 mg (0.0105 mmol)of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate (orTaxotere), the characteristics of which are identical to those describedin the literature, are thereby obtained in a 67% yield.

Although the invention has been described in conjunction with specificembodiments, it is evident that many alternatives and variations will beapparent to those skilled in the art in light of the foregoingdescription. Accordingly, the invention is intended to embrace all ofthe alternatives and variations that fall within the spirit and scope ofthe appended claims. The above references are hereby incorporated byreference.

What is claimed is:
 1. A β-phenylisoserine derivative of general formula (I): ##STR14## in the form of a salt or an ester, in which: Ar represents an aryl radical;R represents a phenyl or α- or β-naphthyl radical unsubstituted or substituted with one or more identical or different atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, and alkoxy radicals containing 1 to 4 carbon atoms, or a radical R₁ --O in which R₁ represents:an unbranched or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms, or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals unsubstituted or substituted with one or more substituents selected from halogen atoms, hydroxyl radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino radicals, morpholino radicals, 1-piperazinyl radicals (unsubstituted or substituted at position 4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals, cyano radicals, carboxyl radicals, and alkoxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, wherein the cycloalkyl, cycloalkenyl, or bicycloalkyl radicals can be unsubstituted or substituted with one or more alkyl radicals containing 1 to 4 carbon atoms; a phenyl or α- or β-naphthyl radical unsubstituted or substituted with one or more atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, or alkyloxy radicals containing 1 to 4 carbon atoms; or a saturated or unsaturated 4- to 6-membered nitrogenous heterocyclic radical unsubstituted or substituted with one or more alkyl radicals containing 1 to 4 carbon atoms; and G₁ represents a --CH₂ --Ph radical in which Ph represents a phenyl radical unsubstituted or substituted with one or more identical or different atoms or radicals selected from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms.
 2. A method of using a compound of formula (I): ##STR15## in the form of a salt or an ester, to prepare a compound of formula (XI): ##STR16## wherein in formulae (I) and (XI): Ar represents an aryl radical;R represents a phenyl or α- or β-naphthyl radical unsubstituted or substituted with one or more identical or different atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, and alkoxy radicals containing 1 to 4 carbon atoms, or a radical R₁ --O in which R₁ represents:an unbranched or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms, or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals unsubstituted or substituted with one or more substituents selected from halogen atoms, hydroxyl radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino radicals, morpholino radicals, 1-piperazinyl radicals (unsubstituted or substituted at position 4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals, cyano radicals, carboxyl radicals, and alkoxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, wherein the cycloalkyl, cycloalkenyl, or bicycloalkyl radicals can be unsubstituted or substituted with one or more alkyl radicals containing 1 to 4 carbon atoms; a phenyl or α- or β-naphthyl radical unsubstituted or substituted with one or more atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, or alkyloxy radicals containing 1 to 4 carbon atoms; or a saturated or unsaturated 4- to 6-membered nitrogenous heterocyclic radical unsubstituted or substituted with one or more alkyl radicals containing 1 to 4 carbon atoms; G₁ represents a --CH₂ --Ph radical in which Ph represents a phenyl radical unsubstituted or substituted with one or more identical or different atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, or alkoxy radicals containing 1 to 4 carbon atoms; and R₄ represents a hydrogen atom or an acetyl radical;the process comprising: a) reacting the product of formula (I) with a baccatin III or 10-deacetylbaccatin III derivative of formula (XII): ##STR17## to obtain a compound of formula (XIII): ##STR18## wherein in formulae (XII) and (XIII): Ar, R, and G₁ are defined as above; G₂ represents a 2,2,2-trichloroethoxycarbonyl radical or a trialkylsilyl radical; and R'₄ represents an acetyl radical or a 2,2,2-trichloroethoxycarbonyl radical;(b) replacing G₂ and, where appropriate, R'₄ with hydrogen atoms to obtain a compound of formula (XIV): ##STR19## wherein Ar, R, and G₁ are defined as above and R₄ represents an acetyl radical or a hydrogen atom; and (c) replacing G₁ with a hydrogen atom to obtain the formula (XI) compound.
 3. The method according to claim 2, wherein step (a) is performed in the presence of a condensing agent or a reactive carbonate and an activating agent in an organic solvent selected from aromatic hydrocarbons, ethers, nitrites, and esters at a temperature between 0 and 90° C.
 4. The method according to claim 2, wherein step (b) is performed with zinc, optionally in combination with copper, in the presence of acetic acid or an inorganic or organic acid dissolved in an aliphatic alcohol when G₂ and/or R'₄ represent a 2,2,2-trichloroethoxycarbonyl radical, or by treatment in an acid medium when G₂ represents a trialkylsilyl radical.
 5. The method according to claim 2, wherein step (c) is performed by hydrogenolysis.
 6. The method according to claim 5, wherein the hydrogenolysis is performed by means of hydrogen in the presence of a catalyst or by action of dichlorodicyanobenzoquinone in an organic solvent. 